Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Applying Pharmacogenomics in Drug Discovery and Development
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druggability and, if possible, their presence and frequency should be assessed in
the patient population. 39 Different types of genetic alterations (genetic variants) may
also exist and respond differently to drugs. For example, the genetic alteration that
causes CML, Bcr-Abl, has three genetic variants: major (M-bcr), minor (m-bcr), and
micro (mu-bcr). 40 It should be noted that the effect does not always decrease druggability,
and that in some cases an increase in druggability of the target is observed.
For example, gefitinib, an inhibitor of epidermal growth factor receptor (EGFR),
has increased efficacy in patients who harbored EGFR-activating mutations; these
mutations promote increased binding between gefitinib and EGFR: that is, increased
druggability. 41 In a clinical trial of gefitinib, non–small cell lung cancer (NSCLC)
patients who harbored the EGFR-activating mutations, typically patients from East
Asia, had a median survival time of 3.1 years compared to 1.6 years in mutationnegative
patients.
In silico (computer-based) analyses and/or screening assays are typically used
for preliminary studies, and these can help reduce costs and expedite drug discovery
(see Figure 4.2 42 for examples of in silico tests). In silico approaches to identifying
drug candidates include similarity searching (using databases to identify
drugs that have been shown to successfully target a family member of the gene
of interest) and quantitative structure–activity relationships (QSARs, models that
help predict the biological activity of a chemical structure). 35,43 Similarity searching
is often preferred as it is more likely that additional information such as toxicity
profile and efficacy data is available for these chemically and structurally similar
drugs (often referred to as “me-too” drugs), and this information can be used to
expedite drug development and reduce costs. Examples of “me-too” drugs include
atenolol and timolol (structurally similar to propranolol), and ranitidine and nizatidine
(structurally similar to cimetidine). A criticism of “me-too” drugs is that they
often do not result in a significant improvement in patient outcomes compared to
their parent drug. 44 In contrast to similarity searching, structure–activity models
allow for the identification of novel drugs and have been instrumental in advancing
the field of drug discovery. For example, QSAR has been used to identify ketolide
derivatives (macrolide antibiotics) that have higher efficacy and lower toxicity. 45
Disease-related
genomics
Target
identification
Target
validation
Lead
discovery
Lead
optimization
Preclinical
tests
Clinical
trials
• Bioinformatics
• Reverse docking
• Protein structure
prediction
• Target
• Library design
druggability • Docking scoring
• Tool compound • De novo design
design • Pharmacophore
• Target flexibility
• QSAR
• In silico ADMET
• 3D-QSAR prediction
• Structure-based • Physiologically based
optimization pharmacokinetic
simulations
FIGURE 4.2 In silico studies can be used at several stages during the drug development
process, including during target identification, target validation, druggability testing (lead
discovery and optimization), and during preclinical tests. The types of in silico studies that
may be performed are outlined in this diagram. (Adapted from Kore PP, et al., Open J Med
Chem, 2, 139–148, 2012.)